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(Circulation. 2009;119:1241-1252.)
© 2009 American Heart Association, Inc.

Heart Failure

Long-Term Cardiac-Targeted RNA Interference for the Treatment of Heart Failure Restores Cardiac Function and Reduces Pathological Hypertrophy

Lennart Suckau, BSc; Henry Fechner, DVM; Elie Chemaly, MD; Stefanie Krohn, BSc; Lahouaria Hadri, PhD; Jens Kockskämper, MD; Dirk Westermann, MD; Egbert Bisping, MD; Hung Ly, MD; Xiaomin Wang, BSc; Yoshiaki Kawase, MD; Jiqiu Chen, MD; Lifan Liang, MD; Isaac Sipo, PhD; Roland Vetter, MD; Stefan Weger, PhD; Jens Kurreck, PhD; Volker Erdmann, PhD; Carsten Tschope, MD; Burkert Pieske, MD; Djamel Lebeche, PhD; Heinz-Peter Schultheiss, MD; Roger J. Hajjar, MD^*; Wolfgang C. Poller, MD^*

From the Department of Cardiology and Pneumology (L.S., H.F., S.K., D.W., X.W., I.S., C.T., H.-P.S., W.C.P.), Department of Pharmacology and Toxicology (R.V.), and Department of Virology (S.W.), Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Cardiovascular Research Center (E.C., L.H., H.L., Y.K., J.C., L.L., D.L., R.J.H.), Mt Sinai School of Medicine, New York, NY; Department of Cardiology (J. Kockskämper, E.B., B.P.), Medical University of Graz, Graz, Austria; and Institute of Biochemistry (J. Kurreck, V.E.), Freie Universität Berlin, Berlin, Germany.

Correspondence to Professor Wolfgang Poller, MD, Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité–University Medicine Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail wolfgang.poller{at}charite.de

Received April 10, 2008; accepted November 21, 2008.

Background— RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. Here, we report on targeted RNAi for the treatment of heart failure, an important disorder in humans that results from multiple causes. Successful treatment of heart failure is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban, a key regulator of cardiac Ca²⁺ homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy uses regulatory RNAs to achieve its effect.

Methods and Results— We describe structural requirements to obtain high RNAi activity from adenoviral and adeno-associated virus (AAV9) vectors and show that an adenoviral short hairpin RNA vector (AdV-shRNA) silenced phospholamban in cardiomyocytes (primary neonatal rat cardiomyocytes) and improved hemodynamics in heart-failure rats 1 month after aortic root injection. For simplified long-term therapy, we developed a dimeric cardiotropic adeno-associated virus vector (rAAV9-shPLB) to deliver RNAi activity to the heart via intravenous injection. Cardiac phospholamban protein was reduced to 25%, and suppression of sacroplasmic reticulum Ca²⁺ ATPase in the HF groups was rescued. In contrast to traditional vectors, rAAV9 showed high affinity for myocardium but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (left ventricular end-diastolic pressure, dp/dt_min, and ) and systolic (fractional shortening) functional parameters to normal ranges. The massive cardiac dilation was normalized, and cardiac hypertrophy, cardiomyocyte diameter, and cardiac fibrosis were reduced significantly. Importantly, no evidence was found of microRNA deregulation or hepatotoxicity during these RNAi therapies.

Conclusions— Our data show for the first time the high efficacy of an RNAi therapeutic strategy in a cardiac disease.

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Clinical Summaries
Circulation 2009 119: 1177-1179. [Extract] [Full Text]